Project Summary/Abstract As the third most prevalent brain disorder, epilepsy affects virtually three million Americans and results in an estimated annual health care cost of $17.6 billion. There are about 150,000 new cases of epilepsy annually diagnosed in the U.S., mostly in children and the elderly. Current antiepileptic drugs (AEDs) dampen seizures mainly via enhancing GABA function or blocking sodium channels. However, the conventional AEDs cause well-documented side effects and lack efficacy in about a third of epilepsy patients. In addition, no current drug has been shown to prevent epileptogenesis, i.e., the development of epilepsy after acute brain insults. Identifying new drug targets and developing novel therapies are urgently needed to achieve the ultimate goal of ?no seizures, no side effects? in the management of epilepsy. We previously demonstrated that prostaglandin E2 (PGE2) via its EP2 receptor subtype plays essential roles in prolonged seizure-induced neuroinflammation and neurodegeneration. We also found that EP2 receptor regulates the expression of a variety of pro-inflammatory genes in microglia likely via cAMP/Epac signaling. A better understanding of inflammatory prostaglandin signaling pathways that contribute to the pathophysiology of seizures and epilepsy might help identify novel drug targets with more specificity. In this proposal, we will test the hypothesis that prostaglandin PGE2 receptor EP2 in microglia mediates seizure-provoked brain inflammation and injury through cAMP/Epac signaling. We will utilize a combination of novel molecular genetics, pharmacology and behavior strategies that we developed in our laboratory to test this hypothesis in rodent models of epilepsy. Successful completion of these studies will provide new insights into the regulation of inflammation and injury in epileptic brain that should be also relevant to many other acute or chronic neurological conditions involving neuroinflammation with elevated COX-2 and PGE2 activities, including stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, etc. More importantly, this research is expected to provide critical information that will guide drug discovery efforts aimed at developing novel therapeutic agents to treat these brain conditions.